The proposed studies will characterize the effect of acute, subacute and chronic infection of cocaine on the neuroendocrine system. The following hypotheses will be tested. (1) Cocaine disrupts the neuroendocrine system by inhibiting serotonergic neurons. (2) Cocaine abuse alters stress-induced activation of the neuroendocrine system by inhibiting serotonergic neurons. (3) The hypothalamic paraventricular nucleus (PVN) is a site of cocaine action on neuroendocrine function. (1) Cocaine is known to inhibit the activity of serotonergic neurons. This laboratory has demonstrated that serotonergic neurons regulate renin, ACTH/corticosterone and prolactin secretion. As a logical extension of our previous work, we will determine how cocaine alters the effect of serotonin releasers and agonists on plasma levels of the aforementioned hormones (Specific Aim 1). (2) Stress increases the secretion of renin, ACTH/corticosterone, and prolactin. An intact serotonergic system is necessary for the full expression of the neuroendocrine responses to stress, as defined by the aforementioned hormones. In light of the known inhibitory effects of cocaine on serotonergic neural activity, we will determine if cocaine modifies neuroendocrine resPonses to stress (Specific Aim 2). The stressor is an "induced defense (fear) reaction". (3) We, and others, have shown that neurons in the PVN play a vital role in stress-induced neuroendocrine activation, and serotonergic nerve terminals in the PVN mediate the effect of stressors on hormone secretions. Specific Aim 3 is designed to determine whether or not serotonergic terminals in the hypothalamic PVN are the site of cocaine action on the neuroendocrine system. This will be examined by measuring neuroendocrine responses to micro- injection of 5-HT agonists into the PVN after injection of acute, subacute and chronic cocaine (i.p.). The proposed studies should clarify the effect of cocaine on the neuroendocrine axis. Furthermore. these studies could lead to new diagnostic tests for deterioration of brain serotonergic neurons and result in improved treatment for cocaine abusers.